A long-term objective of this research has been the development of a clinically meaningful and therapeutically relevant biochemical classification of depressive disorders. A major focus has been on the use of measurements of catecholamines and metabolites, particularly urinary MHPG levels and scores of an empirically-derived discriminant function equation (D-type equation) that includes other urinary catecholamines and metabolites in addition to MHPG. Our previous studies have shown that unipolar depressive disorders may be divided into three subgroups based on pretreatment urinary MHPG levels that predict differential responses to certain antidepressant drugs, and that scores on the D-type equation may identify depressed patients with latent bipolar affective disorders prior to the first clinical episode of mania. Based in part on these findings, the proposed research will: a) test the hypothesis (through clinical follow-up studies) that patients with low scores on the D-type equation have a greater incidence of subsequent episodes of mania, hypomania or schizoaffective psychotic states than patients with high D-type scores; b) compare the incidence of bipolar affective disorders, depressions or alcoholism in first-degree relatives of patients with low versus high scores on the D-type equation; c) test the hypothesis that the anticholinergic properties of antidepressant drugs contribute to their antidepressant effects in patients with elevated pretreatment urinary MHPG levels by comparing the effects of desipramine (weak anticholinergic) with protriptyline (potent anticholinergic) in depressed patients with low, intermediate and elevated urinary MHPG levels; d) test the hypothesis that patients with low pretreatment urinary MHPG levels respond favorably and rapidly to treatment with maprotiline in low doses, whereas those patients with high MHPG levels who respond to maprotiline require higher doses and longer periods of drug administration, while patients with intermediate levels are not responsive to maprotiline; e) determine whether pretreatment scores on the D-type equation are better predictors of differential responses to the above-mentioned antidepressant drugs than are MHPG levels; and f) validate the D-type equation by determining its sensitivity and specificity with respect to data obtained on clinical follow-up, family history data, differential responses to specific antidepressants, and other biochemical measurements including platelet MAO activity and kinetic parameters, platelet 3H-imipramine binding, urinary free cortisol, and dexamethasone suppression test responses.